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PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

17 August 2006. The case for subtyping schizophrenia by genetic study receives support in a paper published in the August issue of the Archives of General Psychiatry. Hugh Gurling of University College London and his multi-institution team found that variations in the gene for pericentriolar material 1 (PCM1) on chromosome 8 are associated with risk of schizophrenia. The researchers also provide imaging evidence that having these schizophrenia-associated variations in PCM1 leads to a different pattern of brain abnormality than is seen in other cases of schizophrenia.

Hunting for genes of small effect
Linkage studies of schizophrenia have pointed to a number of different loci on different chromosomes as being involved in the disorder, and meta-analyses suggest that the inconsistencies reflect heterogeneity of susceptibility genes acting in different individuals and families (see, e.g., Lewis et al., 2003). Similarly, association studies have not consistently replicated the involvement of individual genes. The conclusion geneticists have been able to draw from these findings is that there are going to be several different modes of transmission for different subtypes of schizophrenia.

Chromosome 8 seems to be a particularly good hunting ground for genes involved in schizophrenia. Several regions of the chromosome have been implicated (see, most recently, Walss-Bass et al., 2006), and neuregulin 1 (NRG1), one of the genes of most interest (see SRF related news story), is located in the same region of the chromosome as PCM1 (8p21-22). Also in this region are PPP3CC (calcineurin), DRP2 (dihydropyrimidinase-related protein 2), and FZD3 (frizzled), all of which have been linked to increased likelihood of having schizophrenia.

In their current study, Gurling’s team first revisited their earlier genomewide scan of 13 families with multiple cases of schizophrenia, which had found linkage to 8p21-22 (Gurling et al., 2001). Reanalyzing the data, the researchers found that variation at the microsatellite marker D8S261, located within the PCM1 gene, was associated with schizophrenia. They replicated the association with D8S261 in a case-control sample of 450 patients and 450 controls from London and surroundings, along with statistically significant association between schizophrenia and an additional microsatellite marker and several single nucleotide polymorphism (SNP) markers within the gene. Furthermore, several haplotypes consisting of three or four of these markers showed strongly significant associations with schizophrenia.

Interestingly, the researchers also found an association between the NRG1 gene and schizophrenia in this sample, but the evidence was not as strong as that seen for PCM1. They also report that they found no evidence for susceptibility from the PPP3CC or FZD3 genes.

The researchers went on to confirm the association of D8S261 variation with schizophrenia in a separate U.S. population of 100 schizophrenia and schizoaffective disorder patients and their parents, but they failed to replicate the results in a Scottish case-control sample of 200 cases and 200 controls.

Imaging “PCM1 schizophrenia”
Just what is this PCM1, and how might variations in the gene contribute to schizophrenia? The protein product is a player at the centrosome, the organizing hub of microtubules, meaning that it can assist in, or disrupt, a range of cellular processes from cell division and migration to axonal transport to synaptic function. PCM1 has been known to associate with other molecules that have been investigated in schizophrenia, including Nudel and Lis1 (see Guo et al., 2006), which of course makes it tempting to speculate that it might have ties to DISC1 (see SRF related news story).

In the second phase of the study, Gurling and colleagues chose to look for gross anatomical brain effects of PCM1 genetic variation, using voxel morphometry MRI. They selected two genetically distinct schizophrenia subgroups from the London case-control study for structural imaging: one group whose PCM1 genes harbored two of the schizophrenia-associated microsatellite or SNP marker variants (termed the SZ8 group; n = 14) and another group that displayed none of the marker alleles associated with schizophrenia (SZ0; n = 13).

Consistent with many previous studies, both patient groups showed significant reductions in gray matter compared to controls, both in absolute terms and relative to white matter, but no differences in white matter volume. The two schizophrenia groups also did not differ from each other on these global measures. However, there were clear regional differences. The SZ8 group had significantly lower gray matter volume, relative to controls, in the orbitofrontal cortex, bilaterally. By contrast, the SZ0 group did not differ from controls in this region, but showed lower gray matter volumes in a number of other brain areas.

When the two schizophrenia groups were compared directly, medial orbitofrontal cortex had significantly lower volume in SZ8 versus SZ0 patients. Conversely, left hippocampus, right dorsolateral prefrontal cortex, and the temporal poles of both hemispheres, were reduced in volume in SZ0 versus SZ8 patients.

The pattern of morphologic differences led the authors to speculate that it might be possible to distinguish PCM1-associated schizophrenia from the remainder of patients diagnosed with schizophrenia. For example, orbitofrontal cortex is known to be critical for reward-related or motivational processing. Deficits in these domains might contribute to the constellation of deficits (including greater affective and cognitive deficits, along with poorer outcome) found with greater frequency in families with linkage to 8p21-22, compared to families with linkage to other chromosomal loci (Kendler et al., 2000). But, as the authors point out, the association of PCM1 with schizophrenia needs confirmation in other samples.—Hakon Heimer.

Reference:
Gurling HM, Critchley H, Datta SR, McQuillin A, Blaveri E, Thirumalai S, Pimm J, Krasucki R, Kalsi G, Quested D, Lawrence J, Bass N, Choudhury K, Puri V, O'Daly O, Curtis D, Blackwood D, Muir W, Malhotra AK, Buchanan RW, Good CD, Frackowiak RS, Dolan RJ. Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. Arch Gen Psychiatry. 2006 Aug;63(8):844-54. Abstract

Comments on News and Primary Papers
Comment by:  Akira Sawa, SRF Advisor
Submitted 22 August 2006
Posted 22 August 2006

Many linkage analyses have reproducibly reported 8p21-22 as a linkage hot locus for schizophrenia. The gene coding for neuregulin-1 is regarded as a factor that contributes to the linkage peak, but other genes may also be involved. Dr. Gurling and colleagues have conducted an excellent association study and obtained evidence that the gene coding for pericentriolar material 1 (PCM1) is associated with schizophrenia.

The results from the genetic portions of this are consistent with our unpublished biological study. (The abstract of Kamiya et al. has been submitted to SFN meeting at Atlanta in October 2006.) In exploring protein interactors of disrupted-in-schizophrenia-1 (DISC1), a promising risk factor for schizophrenia and bipolar disorder, we already came across PCM1 as a potential protein interactor of DISC1. This interaction has been confirmed by yeast two-hybrid and biochemical methods. In immunofluorescent cell staining, a pool of DISC1 and PCM1 are co-stained at the centrosome. Therefore, this genetic study is really encouraging us to move beyond our preliminary study on DISC1 and PCM1.

Of interest, Gurling and colleagues reported in the paper that the cases with the PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. This may be in accordance with our previous publication (Sawamura et al., 2005) reporting the alteration in subcellular distribution of DISC1 in the orbitofrontal cortex of the patients with schizophrenia.

Although a possible link of DISC1 and PCM1 in the pathophysiology of schizophrenia is still hypothetical, the intriguing work by Dr. Gurling and colleagues may now open a window in studying the centrosomal “pathway” in association with schizophrenia. Epistatic interactions on DISC1, PCM1, and related molecules may also be of interest for future studies.

View all comments by Akira SawaComment by:  Mary Reid
Submitted 20 August 2006
Posted 23 August 2006

Regarding the possibility that PCM1 may have ties to DISC1, it's of interest that when PCM1 function is inhibited there is reduced targeting of centrin, pericentrin and ninein to the centrosome (1). Miyoshi and colleagues (2) report that their data indicate that DISC1 localizes to the centrosome by binding to kendrin/pericentrinB. Might there be a failure of DISC1 to localize in the centrosome in PCM1 deficiency?

Do these families with PCM1-associated schizophrenia also have a history of scleroderma? It is also of interest that PCM1 is an autoantigen target in scleroderma (3), and there is a report of cerebral involvement of scleroderma presenting as schizophrenia-like psychosis (4).

Abelson Helper Integration Site 1 (AHI1) gene is a candidate gene for schizophrenia and mutations in AHI1 underlie the autosomal recessive Joubert Syndrome in which cerebellar vermis hypoplasia is reported.(5) Increased cerebellar vermis white-matter volume has recently been reported in males with schizophrenia.(6)

It's interesting that mutations in the centrosomal protein nephrocystin-6 may also cause Joubert syndrome and that it activates ATF4. (7) Morris and colleagues (8) find that DISC1 interacts with ATF4 - a schizophrenia locus on 22q13 and ATF5. Perhaps failure of DISC1 to localize to the centrosome due to PCMI deficiency may also result in reduced activation of ATF4/5.

In view of the study by Al Sarraj and colleagues (9) finding that ATF4/5 stimulate asparagine synthetase activity might we suspect that reduced activation of ATF4 and ATF5 in schizophrenia may explain the decreased CSF asparagine levels reported (10) Perhaps asparagine synthetase might be a suitable drug target in schizophrenia. Of further relevance is the processed pseudogene for asparagine synthetase found upstream of GNAL -18p11, a region linked to bipolar disorder and schizophrenia. (11) Hirotsune and colleagues (12) report that an expressed pseudogene regulates messenger-RNA stability of its homologous coding gene.

Might we also suspect a role for DISC1 in oligodendrocyte dysfunction in schizophrenia? Reduced myelination is reported in neonatal rats deprived of asparagine?(13) It would seem relevant however that Mason and colleagues (14) find that ATF5 regulates proliferation and differentiation of oligodendrocytes, with loss of function resulting in accelerated oligodendrocyte differentiation

References:

1. Dammermann A, Merdes A. Assembly of centrosomal proteins and microtubule organization depends on PCM-1. J Cell Biol. 2002 Oct 28;159(2):255-66. Epub 2002 Oct 28. Abstract

2. Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M, Ogawa N. DISC1 localizes to the centrosome by binding to kendrin. Biochem Biophys Res Commun. 2004 May 14;317(4):1195-9. Abstract

3. Bao L, Zimmer WE, Balczon R. Autoepitope mapping of the centrosome autoantigen PCM-1 using scleroderma sera with anticentrosome autoantibodies. Autoimmunity. 1995;22(4):219-28. Abstract

4. Muller N, Gizycki-Nienhaus B, Botschev C, Meurer M. Cerebral involvement of scleroderma presenting as schizophrenia-like psychosis. Schizophr Res. 1993 Aug;10(2):179-81. Abstract (5) Eur J Hum Genet. 2006 Jun 14; [Epub ahead of print] AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. Amann-Zalcenstein D, Avidan N, Kanyas K, Ebstein RP, Kohn Y, Hamdan A, Ben-Asher E, Karni O, Mujaheed M, Segman RH, Maier W, Macciardi F, Beckmann JS, Lancet D, Lerer B. (6) J Psychiatr Res. 2006 Apr 18; [Epub ahead of print] Increased cerebellar vermis white-matter volume in men with schizophrenia. Lee KH, Farrow TF, Parks RW, Newton LD, Mir NU, Egleston PN, Brown WH, Wilkinson ID, Woodruff PW (7) Nat Genet. 2006 Jun;38(6):674-81. Epub 2006 May 7. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA,Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. (8) Hum Mol Genet. 2003 Jul 1;12(13):1591-608. Links DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Morris JA, Kandpal G, Ma L, Austin CP. (9) Biol Chem. 2005 Sep;386(9):873-9. Links Regulation of asparagine synthetase gene transcription by the basic region leucine zipper transcription factors ATF5 and CHOP. Al Sarraj J, Vinson C, Thiel G. (10) Nippon Rinsho. 1992 Jul;50(7):1643-9. Links [Amino acid metabolism in endogenous psychoses: significance of amino acids as neurotransmitter, precursor of monoamines and allosteric regulator of neuro-receptors] Doi N. (11) Mol Psychiatry. 2000 Sep;5(5):495-501. Links Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. Vuoristo JT, Berrettini WH, Overhauser J, Prockop DJ, Ferraro TN, Ala-Kokko L. (12) Nature. 2003 May 1;423(6935):26-8. An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A. (13) Dev Neurosci. 1982;5(4):332-44. Brain development in neonatal rats nursing asparagine-deprived dams. Newburg DS, Fillios LC. (14) Mol Cell Neurosci. 2005 Jul;29(3):372-80. ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mason JL, Angelastro JM, Ignatova TN, Kukekov VG, Lin G, reene LA, Goldman JE.

View all comments by Mary ReidComment by:  Mary Reid
Submitted 10 September 2006
Posted 12 September 2006

Den Hollander and colleagues (1) report that mutations in CEP290-nephrocystin-6 are a frequent cause of Leber's Congenital Amaurosis (LCA). Autistic signs are reported in both Joubert syndrome and LCA (2,3). Perhaps asparagine may be useful for those with LCA and dysmyelination.

References:

1. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP. Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis. Am J Hum Genet. 2006 Sep;79(3):556-61. Epub 2006 Jul 11. Abstract

2. Curless RG, Flynn JT, Olsen KR, Post MJ. Leber congenital amaurosis in siblings with diffuse dysmyelination. Pediatr Neurol. 1991 May-Jun;7(3):223-5. Abstract

3. Rogers SJ, Newhart-Larson S. Characteristics of infantile autism in five children with Leber's congenital amaurosis. Dev Med Child Neurol. 1989 Oct;31(5):598-608. Abstract

View all comments by Mary ReidComment by:  Mary Reid
Submitted 25 September 2006
Posted 28 September 2006

The asparagine synthetase gene has been mapped to 7q21.3 (1). Childhood-onset schizophrenia/autistic disorder has been described in a child with a translocation breakpoint at 7q21. Of further interest is that alcohol/drug abuse, severe impulsivity, paranoid personality, and language delay have been reported in other family members carrying this translocation.

Maybe the increased risk of schizophrenia following famine may be explained by the fact that starvation induces expression of ATF4 and asparagine synthetase. Is there an increased risk of mutation in these genes as a long-term response to famine?

References:

1. Heng HH, Shi XM, Scherer SW, Andrulis IL, Tsui LC. Refined localization of the asparagine synthetase gene (ASNS) to chromosome 7, region q21.3, and characterization of the somatic cell hybrid line 4AF/106/KO15. Cytogenet Cell Genet. 1994;66(2):135-8. Abstract

2. Yan WL, Guan XY, Green ED, Nicolson R, Yap TK, Zhang J, Jacobsen LK, Krasnewich DM, Kumra S, Lenane MC, Gochman P, Damschroder-Williams PJ, Esterling LE, Long RT, Martin BM, Sidransky E, Rapoport JL, Ginns EI. Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21. Am J Med Genet. 2000 Dec 4;96(6):749-53. Abstract

View all comments by Mary Reid

Comments on Related News


Related News: Neuregulin, ErbB4—Levels Normal but Signaling Strengthened in Schizophrenia

Comment by:  Patricia Estani
Submitted 22 June 2006
Posted 22 June 2006
  I recommend the Primary Papers

Related News: Neuregulin, ErbB4—Levels Normal but Signaling Strengthened in Schizophrenia

Comment by:  Cynthia Shannon Weickert, SRF AdvisorVictor Chong
Submitted 8 August 2006
Posted 8 August 2006

In contrast to its once barren form, the table of potential causative genes for schizophrenia is now stocked to feast level (Straub and Weinberger, 2006). In keeping with the culinary theme, we suggest that this recent paper by Chang-Gyu Hahn and Hoau-Yan Wang is “a full course meal”!

Appetizer: An Important Biological Problem
If one assumes that alterations in NRG-1 account for at least some of the liability to developing schizophrenia, then it is only reasonable to look to the NRG-1 receptors for clues as to how and where NRG-1 may be acting. However, there are three known NRG-1 receptors that mediate a myriad of biological functions, almost all of which could be argued to be relevant to schizophrenia pathology. This paper draws our attention to one NRG-1 receptor, ErbB4, showing this receptor to be a probable NRG-1 partner in mediating this pathology. Recent studies provide further support that ErbB4 may be integral to the development of schizophrenia by demonstrating its gene to be a potential susceptibility gene (Norton et al., 2006; Silberberg et al., 2006; Nicodemus et al., in press). So, genetic and neurobiological evidence suggest the authors selected their NRG-1 receptor wisely.

Main Course: A New Approach
The novel postmortem-stimulation approach used by Hahn and colleagues represents an important advance in the field of schizophrenia research. Through extensive validation of this protocol, this research group has paved the way for future experimentation into the molecular activation of proteins within the schizophrenic brain. More specifically, while previous studies have only been able to draw conclusions about the static state of the schizophrenic brain, this article has introduced a novel method for examining dynamic signaling systems in postmortem brains of patients with schizophrenia. For example, based on the finding that certain splice variant ErbB4 mRNAs are elevated in the prefrontal cortex of these individuals (Silberberg et al., 2006), one would assume that ErbB4 protein should also be elevated in these patients. But Hahn et al. demonstrate that schizophrenic individuals show only marginal increases in prefrontal cortical ErbB4 protein levels, which could suggest that ErbB4 protein plays little role in the pathology of schizophrenia. However, using the more dynamic postmortem-stimulation approach, the authors showed that ErbB4 signaling is, in fact, greatly enhanced in the prefrontal cortex of patients with this disease, leading to the alternative interpretation that ErbB4 protein may play significant roles in schizophrenia. In other words, this postmortem-stimulation protocol extends the examination of human postmortem brain protein from quantification to the functional level. We view this method as a powerful approach that will be important in translating genetic susceptibility into molecular mechanisms of the disease process. The postmortem-stimulation approach also gave rise to the observation that schizophrenic patients exhibit reduced prefrontal cortical NMDA receptor signaling capacity. This finding is highly significant because it is the first evidence directly linking reduced prefrontal cortical NMDA receptor function to schizophrenia. However, whether NRG-1-ErbB4 signaling is a major contributor to NMDA receptor hypofunction is debatable since the attenuation of NMDA receptor phosphorylation by NRG-1 appears proportionally similar between controls and schizophrenic patients.

Side Dish: Dealing with Antipsychotic Drugs
Since most patients with schizophrenia have received antipsychotic drugs and these agents can have profound impact on brain systems, it is essential to determine whether changes observed in the brains of patients with schizophrenia are secondary to antipsychotic drug exposure. To address this issue, the authors took two important steps. Firstly, Hahn et al. examined whether antipsychotic drug exposure affected prefrontal cortical ErbB4 expression or signaling in their human study group and found no correlation between antipsychotic drug treatment and either of these measured variables. Secondly, the authors examined antipsychotic drug effects on prefrontal cortical ErbB4 signaling in mice implanted with a haloperidol-containing bioabsorbable polymer, which has a number of advantages. For example, it allows for long-term treatment of the animals (12 weeks) while minimizing handling. This duration of exposure is arguably more appropriate than some schedules used to examine chronic effects of antipsychotic drugs in rodents. Remarkably, haloperidol treatment caused a reduction in ErbB4 signaling in the mice, suggesting that a decrease in ErbB4 signaling is associated with the therapeutic effects of antipsychotic agents. What may have been more informative is to show whether haloperidol had any effect on ErbB4 protein levels without NRG-1 treatment. In addition, the authors could have considered examining antipsychotic drug effect in mice whose ages were more reflective of those of the investigated human cohort, which consisted of elderly individuals (65-92 years). Furthermore, while their analysis of antipsychotic drugs on ErbB4 expression and signaling in postmortem brain was noteworthy, the authors only examined the effects of antipsychotic drugs taken in the final month before death in a very aged sample population. Thus, it is difficult to ascertain whether ErbB4 expression or signaling is not affected by lifetime antipsychotic drug treatment, which can result in cellular and molecular consequences that can remain long after termination of therapy.

Dessert: Challenging the Field
Of course, the first thing the field needs to do is attempt to replicate these findings in another cohort of patients with schizophrenia compared to controls. Careful attention to matching for age, PMI, and gender, etc., as was done in this study, is critical. We suggest that using a young cohort of patients would help rule out potential confounds such as associated dementia and interaction with the aging process. However, it is recognized that many other potential confounds will still remain in most studies comparing schizophrenics to unaffected controls. These confounds include suffering from years of an unremitting illness that compromises normal social and environmental stimulation, increased incidence of cigarette smoking among patients with schizophrenia, and years of antipsychotic drug exposure. When the finding of schizophrenia-associated increased ErbB4 signaling capacity is replicated, then the task at hand will be to determine how possible genetic changes in the DNA at the NRG-1 or ErbB4 locus (representing one etiological route) could lead to a “hyperactivatable” ErbB4.

Doggie Bag: Nagging Questions
One of the caveats we would like to raise in attempting to link molecular neurobiological changes found in schizophrenic brain tissue with possible changes in DNA is that causative variants in any one susceptibility gene are expected to occur only in a minority of schizophrenic patients. Most measures performed on postmortem schizophrenic brains are made on small sample sizes, which likely show much heterogeneity in terms of etiology. In other words, only a handful of patients in this study would be expected to have a faulty NRG-1 gene; yet this subpopulation shows alterations in ErbB4 signaling as a group. The logical extension of this observation may be that there are multiple routes by which ErbB4 could be “hyperactivatable” (i.e., not solely through NRG-1 genetic liability). To sort this out, we need to work from the gene forward, and thus there is a need to identify causative variants in susceptibility genes and to use these as starting points for basic mechanistic molecular and cellular studies.

View all comments by Cynthia Shannon Weickert
View all comments by Victor Chong

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  David J. Porteous, SRF Advisor
Submitted 11 February 2009
Posted 12 February 2009

The answer is unequivocally, “yes”
In co-highlighting the papers from Need et al., 2009, and Tomppo et al., 2009, you pose the question “CNV’s, interacting loci or both?” to which my immediate answer is an unequivocal “yes,” but it actually goes further than that. These two studies, interesting in their own rights, add just two more pieces of evidence now accumulated from case only, case-control, and family-based linkage on the genetic architecture of schizophrenia. Thus, we can reject with confidence a single evolutionary and genetic origin for schizophrenia. If it were so, it would have been found already by the plethora of genomewide studies now completed, studies specifically designed to detect causal variants, should they exist, which are both common to most if not all subjects and ancient in origin—the Common Disease, Common Variant (CDCV) hypothesis.

Moreover, for DISC1, NRG1, NRXN1, and a few others, the criteria for causality are met in some subjects, but none of these is the sole cause of schizophrenia. Their net contributions to individual and population risk remain uncertain and await large scale resequencing as well as SNP and CNV studies to capture the totality of genetic variation and how that contributes to the incidence of major mental illness. Meanwhile, nosological and epidemiological evidence has also forced a re-evaluation of the categorical distinction between schizophrenia and bipolar disorder, let alone schizoaffective disorder (Lichtenstein et al., 2009).

In this regard, DISC1 serves again as an instructive paradigm, with good evidence for genetic association to schizophrenia, BP, schizoaffective disorder, and beyond (Chubb et al., 2008). The study by Hennah et al. (2008) added a further nuance to the DISC1 story by demonstrating intra-allelic interaction. Tomppo et al. (2009) now build upon their earlier evidence to show that DISC1 variants affect subcomponents of the psychiatric phenotype, treated now as a quantitative than a dichotomous trait. In much the same way and just as would be predicted, DISC1 variation also contributes to normal variation in human brain development and behavior (e.g., Callicott et al., 2005). Self-evidently, different classes of genetic variants (SNP or CNV, regulatory or coding) will have different biological and therefore psychiatric consequences (Porteous, 2008).

That Need et al. (2009) failed to replicate previous genomewide association studies (or find support for DISC1, NRG1, and the rest) is just further proof, if any were needed, that there is extensive genetic heterogeneity and that common variants of ancient origin are not major determinants of individual or population risk (Porteous, 2008). Variable penetrance, expressivity, and gene-gene interaction (epistasis) all need to be considered, but these intrinsic aspects of genetic influence are best addressed by family studies (currently lacking for CNV studies) and poorly addressed by large-scale case-control genomewide association studies. Power to test the CDCV hypothesis may increase with increasing numbers of subjects, but so does the inherent heterogeneity, both genetic and diagnostic.

That said, genetics is without doubt the most incisive tool we have to dissect the etiology of major mental illness. The criteria for success (and certainly for causality, rather than mere correlation) must be less about the number of noughts after the “p” and much more about the connection between candidate gene, gene variant, and the biological consequences for brain development and function. In this regard, both studies have something to say and offer.

References:

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. 2009 Lancet 373:234-9. Abstract

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. Mol Psychiatry. The DISC locus in psychiatric illness. 2008 Jan;13(1):36-64. Epub 2007 Oct 2. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA,Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. 2005 Proc Natl Acad Sci U S A. 2005 102:8627-32. Abstract

Porteous D. Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. 2008 Curr Opin Genet Dev. 18:229-34. Abstract

View all comments by David J. Porteous

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Pamela DeRosseAnil Malhotra (SRF Advisor)
Submitted 19 February 2009
Posted 22 February 2009

The results reported by Tomppo et al. and Need et al. collectively instantiate the complexities of the genetic architecture underlying risk for psychiatric illness. Paradoxically, however, while the results of Need et al. suggest that the answer to the complex question of risk genes for schizophrenia (SZ) may be found by searching a very select population for rare changes in genetic sequence, the results of Tomppo et al. suggest that the answer may be found by searching for common variants in large heterogeneous populations. So which is it? Is SZ the result of rare, novel genetic mutations or an accumulation of common ones? Such a conundrum is not a novel predicament in the process of scientific inquiry and such conundrums are often resolved by the reconciliation of both opposing views. Thus, if we allow history to serve as our guide it seems reasonable that the answer to the current question of what genetic mechanisms are responsible for SZ, is that SZ is caused by both rare and common variants.

Although considerable efforts, by our lab and others, are currently being directed towards seeking the type of rare variants that Need et al. suggest may be responsible for risk for SZ, a less concerted effort is being directed towards parsing the effects of more specific, common genetic variations. To date, there are limited data seeking to elucidate the effects of previously identified risk variants for SZ on phenotypic variation within the diagnostic group. The data that are available, however, suggest that risk variants do influence phenotypic variation. Our work with DISC1, for example, has produced relatively robust, and replicated findings linking variation in the gene to cognitive dysfunction (Burdick et al., 2005) as well as an increased risk for persecutory delusions in SZ (DeRosse et al., 2007). Similarly, our work with DTNBP1 indicates a strong association between variants in the gene and both cognitive dysfunction (Burdick et al., 2006) and negative symptoms in SZ (DeRosse et al., 2006). Moreover, the risk for cognitive dysfunction associated with the DTNBP1 risk genotype was also observed in a sample of healthy individuals. Thus, it seems conceivable that genetic variation associated with phenotypic variation within a diagnostic group may also be associated with similar, sub-syndromal phenotypes in non-clinical samples.

The data reported by Tomppo et al. provide support for the utility of parsing the specific effects of genetic variants on phenotypic variation and extend this approach to populations with sub-syndromal psychiatric symptoms. Such an approach is attractive in that it allows us to study the effects of genotype on phenotype without the confound imposed by psychotropic medications. Although the current data linking genes to specific dimensions of psychiatric illness are provocative, the study groups utilized are comprised of patients undergoing varying degrees of pharmacological intervention. Thus, in these analyses quantitative assessment of psychosis is to some extent confounded by treatment history and response. By measuring lifetime history of symptoms, which for most patients includes substantial periods without effective medication, many studies (including our own) may partially overcome this limitation. Still, assessment of the relation between genetic variation and dimensions of psychosis in study groups not undergoing treatment with pharmacological agents would be a compelling source of confirmation for these preliminary findings.

Perhaps most importantly, the data reported by Tomppo et al. suggest that previously identified risk genes should not be marginalized but rather, should be studied in non-clinical samples to identity phenotypic variation that may be related to the signs and symptoms of psychiatric illness.

References:

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport. 2005; 16(12):1399-402. Abstract

Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM, Kucherlapati R, Malhotra AK. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet. 2006; 15(10):1563-8. Abstract

DeRosse P, Hodgkinson CA, Lencz T, Burdick KE, Kane JM, Goldman D, Malhotra AK. Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol Psychiatry. 2007; 61(10):1208-10. Abstract

DeRosse P, Funke B, Burdick KE, Lencz T, Ekholm JM, Kane JM, Kucherlapati R, Malhotra AK. Dysbindin genotype and negative symptoms in schizophrenia. Am J Psychiatry. 2006; 163(3):532-4. Abstract

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Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  James L. Kennedy, SRF Advisor (Disclosure)
Submitted 25 February 2009
Posted 25 February 2009

Has anyone considered the possibility that the CNVs found to be elevated in schizophrenia versus controls could be a peripheral effect and perhaps not present in brain tissue? For example, the diet of the typical schizophrenia patient is poor, and it is conceivable that chronic folate deficiency could predispose to problems in DNA structure or repair in lymphocytes. Thus, the CNVs could be an effect of the illness, and not a cause. Someone needs to do the experiment that compares CNVs in blood to those in the brain of the same individual. And then we need studies of the stability of CNVs over the lifetime of an individual.

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Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Kevin J. Mitchell
Submitted 2 March 2009
Posted 2 March 2009

The papers by Need et al. and Tomppo et al. seem to present conflicting evidence for the involvement of common or rare variants in the etiology of schizophrenia.

On the one hand, Need et al., in a very large and well-powered sample, find no evidence for involvement of any common SNPs or CNVs. Importantly, they show that while any one SNP with a small effect and modest allelic frequency might be missed by their analysis, the likelihood that all such putative SNPs would be missed is vanishingly small. They come to the reasonable conclusion that common variants are unlikely to play a major role in the etiology of schizophrenia, except under a highly specific and implausible genetic model. Does this sound the death knell for the common variants, polygenic model of schizophrenia? Yes and no. These and other empirical data are consistent with theoretical analyses which show that the currently popular purely polygenic model, without some gene(s) of large effect, cannot explain familial risk patterns (Hemminki et al., 2007; Hemminki et al., 2008; Bodmer and Bonilla, 2008). It has been suggested that epistatic interactions may generate discontinuous risk from a continuous distribution of common alleles; however, while comparisons of risk in monozygotic and dizygotic twins are consistent with some contribution from epistasis, they are not consistent with the massive levels that would be required to rescue a purely polygenic mechanism, whether through a multiplicative or (biologically unrealistic) threshold model.

Thus, it seems most parsimonious to conclude that most cases of schizophrenia will involve a variant of large effect. As such variants are likely to be rapidly selected against, they are also likely to be quite rare. The findings of specific, gene-disrupting CNVs or mutations in individual genes in schizophrenia cases by Need et al. and numerous other groups support this idea. Excitingly, they also have highlighted specific molecules and biological pathways that provide molecular entry points to elucidate pathogenic mechanisms. The possible convergence on genes interacting with DISC1, including PCM1 and NDE1 in the current study, provides further support for the importance of this pathway, though, clearly, there may be many other ways to disrupt neural development or function that could lead to schizophrenia. (Conversely, it is becoming clearer that many of the putative causative mutations identified so far predispose to multiple psychiatric or neurological conditions.)

Despite the likely involvement of rare variants in most cases of schizophrenia, it remains possible that common alleles could have a modifying influence on risk—indeed, one early paper commonly cited as supporting a polygenic model for schizophrenia actually provided strong support for a model of a single gene of large effect and two to three modifiers (Risch, 1990). A rare variants/common modifiers model would be consistent with the body of literature on modifying genes in model organisms, where effects of genetic background on the phenotypic expression of particular mutations are quite common and can sometimes be large (Nadeau, 2001). Whether such genetic background effects would be mediated by common or rare variants is another question—there is certainly good reason to think that rare or even private mutations may make a larger contribution to phenotypic variance than previously suspected (Ng et al., 2008; Ji et al., 2008).

Nevertheless, common variants are also likely to be involved, and these effects might be detectable in large association studies, though they would be expected to be diluted across genotypes. This might explain inconsistent findings of association of common variants with disease state for various genes, including COMT, BDNF, and DISC1, for example. This issue has led some to look for association of variants in these genes with endophenotypes of schizophrenia in the general population—psychological or physiological traits that are heritable and affected by the symptoms of the disease, such as working memory, executive function, or, in the study by Tomppo et al., social interaction.

These approaches have tended to lead to statistically stronger and more consistent associations and are undoubtedly revealing genes and mechanisms contributing to normal variation in many psychological traits. How this relates to their potential involvement in disease etiology is far from clear, however. The implication of the endophenotype model is that the disorder itself emerges due to the combination of minor effects on multiple symptom parameters (Gottesman and Gould, 2003; Meyer-Lindenberg and Weinberger, 2006). An alternative interpretation is that these common variants may modify the phenotypic expression of some other rare variant, either due to their demonstrated effect on the psychological trait in question or through a more fundamental biochemical interaction, but that in the absence of such a variant of large effect, no combination of common alleles would lead to disease.

References:

Hemminki K, Försti A, Bermejo JL. The 'common disease-common variant' hypothesis and familial risks. PLoS ONE. 2008 Jun 18;3(6):e2504. Abstract

Hemminki K, Bermejo JL. Constraints for genetic association studies imposed by attributable fraction and familial risk. Carcinogenesis. 2007 Mar;28(3):648-56. Abstract

Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008 Jun;40(6):695-701. Abstract

Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222-8. Abstract

Nadeau JH. Modifier genes in mice and humans. Nat Rev Genet. 2001 Mar;2(3):165-74. Abstract

Ng PC, Levy S, Huang J, Stockwell TB, Walenz BP, Li K, Axelrod N, Busam DA, Strausberg RL, Venter JC. Genetic variation in an individual human exome. PLoS Genet. 2008 Aug 15;4(8):e1000160. Abstract

Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008 May;40(5):592-9. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Abstract

Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci. 2006 Oct;7(10):818-27. Abstract

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